Resistance Is Futile

CHICAGO, ILLINOIS--Antibiotics have saved countless lives since Alexander Fleming discovered penicillin in 1927. But in recent years, microbes have responded by developing resistance to many of the most powerful antibiotics, threatening to undermine one of modern medicine's greatest achievements. This evolution of antimicrobial resistance may one day become a thing of the past. California-based researchers reported here today at the semiannual meeting of the American Chemical Society that they've discovered compounds that inhibit the ability of bacteria to produce mutations in their genetic code. The compounds are not antibiotics in themselves. But they could lead to future medicines that could be given alongside powerful antibiotics to prevent bugs from quickly outwitting the drugs.

The new compounds evolved out of the discovery more than 30 years ago that deleting certain genes in bacteria prevents the microbes from evolving resistance when exposed to antibiotics. Biologists later found that when microbes are not under such antibiotic pressure, they copy their DNA using enzymes known as DNA polymerases that make very few mistakes. But when the pressure is on, the bugs turn to normally dormant DNA polymerases that are far more error prone. These errors create genetic mutations in their progeny, some of which prove beneficial, and thereby encourage the selection of new traits such as antibiotic resistance.

Prompted by those results, 2 years ago Floyd Romesberg, a chemist at the Scripps Research Institute in San Diego, California, and colleagues reported that both in vitro and animal studies showed that a gene called LexA serves as one of the key "on" switches for the error-prone DNA polymerase. For their current work, the Scripps researchers looked for small, druglike molecules that inhibit LexA and thereby stymie mutations in bugs exposed to ciprofloxacin, an antibiotic that itself prevents DNA replication. After screening more than 100,000 compounds, the researchers found several potent LexA inhibitors that all but halt the ability of bacteria to mutate and also easily get inside microbial cells, a notoriously difficult challenge for would-be drugs.

The new work is "provocative," says Scott Singleton, a medicinal chemist at the University of North Carolina. "What this would do is make other drugs act more potently and slow down a bacteria's natural ability to respond to a drug," he says. That could prove a boon for halting the worrisome spread of bacteria resistant to vancomycin, an antibiotic that doctors are trying to safeguard as a last line of defense against pathogens. The new compounds are not ready for clinical trials yet. But Romesberg recently launched a biotech company called Achaogen in South San Francisco to commercialize the technology.

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